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Angiogenesis requires integration of cues from growth factors, extracellular matrix (ECM) proteins, and their receptors in endothelial cells. In the present study, we show that the adaptor protein Shc is required for angiogenesis in zebrafish, mice, and cell-culture models. Shc knockdown zebrafish embryos show defects in intersegmental vessel sprouting in the trunk. Shc flox/flox; Tie2-Cre mice display reduced angiogenesis in the retinal neovascularization model and in response to VEGF in the Matrigel plug assay in vivo. Functional studies reveal a model in which Shc is required for integrin-mediated spreading and migration specifically on fibronectin, as well as endothelial cell survival in response to VEGF. Mechanistically, Shc is required for activation of the Akt pathway downstream of both integrin and VEGF signaling, as well as for integration of signals from these 2 receptors when cells are grown on fibronectin. Therefore, we have identified a unique mechanism in which signals from 2 critical angiogenic signaling axes, integrins and VEGFR-2, converge at Shc to regulate postnatal angiogenesis.

Original publication

DOI

10.1182/blood-2011-10-384560

Type

Journal article

Journal

Blood

Publication Date

23/02/2012

Volume

119

Pages

1946 - 1955

Keywords

Animals, Apoptosis, Blotting, Western, Cell Movement, Cells, Cultured, Embryo, Nonmammalian, Extracellular Matrix, Female, Fibronectins, Gene Knockdown Techniques, Human Umbilical Vein Endothelial Cells, Humans, Integrins, Intercellular Signaling Peptides and Proteins, Male, Mice, Mice, Knockout, Neovascularization, Physiologic, Proto-Oncogene Proteins c-akt, Shc Signaling Adaptor Proteins, Signal Transduction, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factor Receptor-2, Zebrafish, Zebrafish Proteins